The present invention relates to the use of α1L-agonists for treating urinary incontinence, particularly stress incontinence.
The cause of stress incontinence in women is usually weakness of the pelvic floor, e.g. after numerous difficult births. However, it may also be due to nerve disorders of the pelvic floor, a congenitally short urethra or, occasionally, damage to the sphincter caused by surgery. The reduction in the oestrogen levels post-menopause further encourages stress incontinence.
The term stress incontinence refers to a sudden loss of urine, which is caused by incompetence of the bladder outlet during unobtrusive movement of the bladder as a result of interabdominal increases in pressure due to coughing, pressing, sneezing, heavy lifting, etc.
Surprisingly, it has been found that the α1L-subtype of the adrenergic receptor has a significant effect on the continence mechanism of urether tonicisation.
The invention relates to the use of α1L-adrenoceptor agonists for treating urinary incontinence, particularly stress incontinence, and for preparing drugs for treating urinary incontinence, particularly stress incontinence. It is particularly interesting to use amino imidazolines of general formula and the pharmacologically acceptable acid addition salts thereof.
In general formula I    Y denotes an optionally substituted phenyl or napthyl group or    Y denotes a 5- or 6-membered, optionally fully unsaturated, optionally substituted heterocyclic ring which contains oxygen, sulphur or nitrogen as heteroatoms, and    X denotes —NH—, —CH2—, —OCH2—, —O—CHCH3—, —CH═N—NH—, —N═N— or —NZ—, wherein Z=—CH2—CH═CH2 or cyclopropylmethyl.
Preferred compounds are those wherein X is —NH— and/or Y is an optionally substituted thienyl, furyl, pyrrole, tetrahydropyrrole, pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl, imidazolyl, imidazolinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, isothiazolyl, pyrimidinyl, thiazolyl, thiadiazinyl or piperidinyl, bound to the group X via a C atom. It is preferred to use tiamenidine.
Preferred compounds for this purpose are imidazolines of general formula or imidazolines of general formula wherein    R1, R2, R3, R4 and R5 denote, independently of one another:    hydrogen, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C3-6-cycloalkyl, preferably cyclopropyl, C1-6-alkoxy, preferably C1-4-alkoxy, most preferably methoxy, halogen, preferably chlorine or bromine, —CF3, —OCF3 or —NR6R7 wherein            R6 denotes hydrogen, C3-6-cycloalkyl, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, or C2-4-acyl, most preferably acetyl,        R7 -denotes hydrogen, C3-6-cycloalkyl, preferably cyclopropyl, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, or C2-4-acyl, most preferably acetyl; or        R6 and R7 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two further heteroatoms selected from oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C1-4-alkyl, preferably methyl;        or R6 and R7 together with the nitrogen atom form phthalimido; or            R1 and R2 together form a fused pyrazole of formula             wherein R8 is C1-3-alkyl, preferably methyl;or a fused thiadiazole of formula             wherein R3, R4 and R5 are as hereinbefore defined, and preferably denote hydrogen,and the pharmacologically acceptable acid addition salts thereof.
Formulae I and I′ and Ib and II are equivalent tautomeric structures. The preparation of one structure (e.g. Ib) includes the other structure (e.g. II) in each case.
Also preferred are imidazolines of general formula Ib wherein    R1 denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromine or CF3,    R2 denotes methyl, fluorine, chlorine, bromine or —NR6R7, wherein    R6 denotes hydrogen, C1-4-alkyl, preferably methyl, C2-4-acyl, preferably acetyl and    R7 denotes hydrogen, C1-4-alkyl, preferably methyl, C2-4-acyl, preferably acetyl or    R6 and R7 together with the nitrogen atom form phthalimido;    R3 denotes hydrogen, fluorine, chlorine, bromine, C1-4-alkyl, preferably methyl, NH2 or cyclopropyl;    R4 denotes hydrogen, C1-4-alkyl, preferably methyl, fluorine, chlorine, bromine or CF3;    R5 denotes hydrogen, C1-4-alkyl, preferably ethyl or methyl, fluorine, chlorine, bromine or CF3; or    R1 and R2 together form a fused pyrazole of formula      wherein R8 is methyl,    or a fused thiadiazole of the formula      wherein R3, R4 and R5 are as hereinbefore defined, and preferably represent hydrogen; particularly those wherein    R1 is hydrogen or methyl;    R2 is methyl, chlorine, CF3, NH2 or N(CH3)2;    R3 is hydrogen, methyl, chlorine or bromine;    R4 is hydrogen;    R5 is hydrogen, methyl, methoxy, chlorine or bromine.
Particular mention should be made of the use of    2-(3-dimethylamino-2-methylphenylimino)imidazolidine,    2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,    2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine,    2-(3-amino-2-methylphenylimino)-imidazolidine or    2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.
Examples of heterocyclic groups —NR6R7 are as follows:    pyrrole, Δ2-pyrroline, Δ3-pyrroline, tetrahydropyrrole, pyrrolidine, pyrrolidinone, imidazole, imidazoline, 1,3-thiazole, piperidine, piperazine, 4-C1-4-alkylpiperazine, C1-4-alkylpiperazine, 2,5-diketopiperazine, preferably N-methylpiperazine, morpholine, thiomorpholine, phthalimido or succinimido.
Examples of alkyl within the above definitions, including those which are components of other groups, are branched or unbranched C1-6-alkyl groups, e.g. methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, n-pentyl, isopentyl, neopentyl, hexyl and isohexyl.
Cycloalkyl generally represents a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms which may optionally be substituted with a halogen atom or several halogen atoms, a hydroxy group, an alkyl group, preferably methyl, which may be the same as or different from one another. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.
Some of the imidazolines defined in general formula Ib are new. The invention therefore also relates to new substituted 2-phenylimino-imidazolidines, their use in pharmaceutical compositions and to processes for preparing them.
2-(Phenylimino)-imidazolidines, the preparation thereof and their use as pharmaceutical compositions are known, for example from German Patent Application Nos. DE-OS-19 29 950 and DE-OS-23 16 377, in which the hypotensive properties of the compounds described are particularly emphasised.
New substituted 2-(phenylimino)-imidazolidines of general formula II have surprising pharmacological properties and are particularly suitable for treating urinary incontinence.
The invention thus relates to compounds of general formula II wherein    R1 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C3-6-cycloalkyl, preferably cyclopropyl, C1-6-alkoxy, preferably C1-4-alkoxy, most preferably methoxy, halogen, preferably chlorine or bromine, —CF3 or —OCF3;    R2 denotes —NR6R7 wherein            R6 denotes hydrogen, C3-6-cycloalkyl, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C2-4-acyl, most preferably acetyl;        R7 denotes hydrogen, cyclopropyl, C3-6-cycloalkyl, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C2-4-acyl, most preferably acetyl; or        R6 and R7 together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two additional heteroatoms selected from the group of oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C1-4-alkyl, preferably methyl; or R6, and R7 together with the nitrogen atom from phthalimido;            R3 denotes hydrogen, halogen, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C1-6-alkoxy, preferably C1-4-alkoxy, most preferably hydrogen, methoxy, —CF3 or —OCF3;    R4 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, hydrogen or halogen;    R5 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl, most preferably methyl, C1-6-alkoxy, preferably C1-4-alkoxy, most preferably methoxy, halogen, —CF3 or —OCF3,and the pharmacologically acceptable acid addition salts thereof, with the exception of 2-(3-diethylamino-2-methyl)-imidazolidine.
Preferred compounds of general formula II are those wherein    R1 denotes hydrogen, C1-4-alkyl, cyclopropyl, C1-4-alkoxy, halogen, CF3 or —OCF3;    R2 denotes —NR6R7 wherein    R6 is hydrogen, C3-6-cycloalkyl, C1-4-alkyl or acetyl,    R7 is hydrogen, cyclopropyl C1-4-alkyl or acetyl, or    R6 and R7 together with the nitrogen atom form phthalimido;    R3 is hydrogen, halogen, C1-4-alkyl, C1-4-alkoxy, CF3 or —OCF3;    R4 is hydrogen, C1-4-alkyl, methyl, halogen;    R5 is hydrogen, C1-4-alkyl, C1-4-alkoxy, halogen, CF3 or —OCF3; particularly those wherein    R1 is hydrogen, C1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF3;    R2 denotes —NR6R7 wherein    R6 is hydrogen, cyclopropyl, C1-4-alkyl, preferably methyl,    R7 denotes hydrogen, C1-4-alkyl, preferably methyl, or R6 and R7 together with the nitrogen atom form phthalimido;    R3 denotes hydrogen, C1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF3;    R4 denotes hydrogen, C1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine;    R5 denotes hydrogen, C1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF3; particularly those wherein    R1 is hydrogen or methyl,    R2 is —NR6R7 wherein    R6 and R7 independently of each other denote hydrogen, methyl or methoxy or    R6 and R7 together with the nitrogen atom form phthalimido;    R3 denotes hydrogen, methyl, fluorine, chlorine or bromine;    R4 denotes hydrogen,    R5 denotes hydrogen, methyl, chlorine or bromine;and the pharmacologically acceptable acid salts thereof, especially the hydrobromides or hydrochlorides thereof.
Particular mention should be made of the following compounds, for example:    2-(3-dimethylamino-2-methylphenylimino)imidazolidine,    2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,    2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine and    2-(3-amino-2-methylphenylimino)-imidazolidine.
The compounds of general formula I and II may be prepared according to analogous processes known per se from the prior art. A selection of the preferred processes are shown in the following synthetic schemes with reference to concrete Examples. 
The preferred processes for preparing the compounds according to the invention will be explained with reference to individual Examples. 
The methylation of the starting material, 2-methyl-3-nitroaniline, may also be carried out analogously to the Leuckart-Wallach reaction using HCOOH/CH2O or using dimethylcarbonate instead of dimethylsulphate.
Compound 2 can be prepared by bromination of compound 1 under conventional reaction conditions 
The following synthetic scheme illustrates the preparation of compounds 2, 3 and 4
Other alternative methods of synthesis are illustrated below. 
Compound 5 and compounds of similar structure can be prepared analogously to a method described by N. R. Ayyangar (Synthesis 1987, 64). 